Hydrogen sulfide attenuates diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor

Abstract

Diabetic neuropathic pain is a frequent complication of diabetic neuropathy. The specific manifestations of diabetic neuropathic pain include spontaneous pain and hyperalgesia, which seriously affect the quality of life of patients. Previous publications have shown that H2S has both pro-nociceptive and anti-nociceptive effects. This present investigation aimed to examine the anti-nociceptive effect of H2S on diabetic neuropathic pain. We established a diabetic neuropathic pain animal model with high-glucose, high-fat diet, and STZ, then treated rats with different concentrations of H2S and inhibitors of NOS, sGC, PKG, and opioid receptors. The mechanical allodynia and thermal hyperalgesia of rats were measured to assess the anti-nociceptive effects of H2S. The mRNA and protein expression of NOS and PKG1 were measured to explore their roles in the anti-nociceptive action of H2S. The results revealed that inhalation of H2S gas had anti-nociceptive effect in diabetic neuropathic pain model rats without affecting the blood glucose level and body mass. It increased the mRNA and protein level of nNOS, and the inhibitor of nNOS, 7-NI, abolished the anti-nociceptive effect of H2S. Furthermore, inhibitors of sGC and PKG could also abolish the anti-nociceptive effect of H2S. The expression of PKG1 was found to be increased by H2S, which was reversed by the inhibitors of nNOS, sGC, and PKG. Finally, CTOP, a μ-opioid receptor antagonist, abolished the anti-nociceptive effect of H2S, indicating that the μ-opioid receptor plays a role in the anti-nociceptive effect of H2S. In conclusion, the findings of this investigation suggest that hydrogen sulfide may attenuate the diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor. Impact statement There are currently approximately 425 million diabetic patients worldwide, of which approximately 90% of patients with diabetes suffer from neuropathy. Diabetic neuropathic pain (DNP) is a common complication of diabetic neuropathy. Nearly half of the patients hospitalized with diabetes have pain symptoms or symptoms related to neurological injury, and the incidence increases with age and diabetic duration. Anti-DNP analgesics have either limited therapeutic effects or serious side effects or lack of clinical trials, which has limited their application. Physiopathological mechanisms and treatment of DNP remain a significant challenge. The present confirmed that inhalation of H2S may attenuate the diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor. It provides us the animal study foundation for the application of H2S on the treatment of DNP and clarifies some target molecules in the pain modulation of DNP.

Hydrogen Sulfide Increases the Analgesic Effects of µ- and δ-Opioid Receptors during Neuropathic Pain: Pathways Implicated

“…These results suggest the participation of the endogenous opioid system in the antiallodynic and antihyperalgesic effects induced by slow-releasing H 2 S donors during neuropathic pain. Our findings are consistent with the reversion of the antinociceptive actions of inhaled H 2 S with the administration of MOR antagonists in rats with diabetic neuropathy [36], and with the blockade of the analgesia induced by Na2S, another H 2 S releaser, with pre-treatment with selective antisense oligodeoxynucleotide probes against DOR and MOR [37]. This suggests that β-endorphins and enkephalins may be involved in the analgesic actions of H 2 S donors during nerve injury-induced neuropathic pain in mice.…”

The Beneficial Effects of Heme Oxygenase 1 and Hydrogen Sulfide Activation in the Management of Neuropathic Pain, Anxiety- and Depressive-like Effects of Paclitaxel in Mice

“…These data are in accordance with the analgesic actions of CoPP and/or CORM-2 (a slow CO releaser) in mice with inflammatory pain or nerve-injury-induced neuropathic pain [ 37 , 38 ], and in animals with vincristine-induced neuropathic pain [ 11 , 12 ]. Our results also agree with the demonstrated analgesic actions of other slow-releasing H 2 S donors, such as isothiocyanates, during osteoarthritis and neuropathic pain [ 17 , 18 , 39 ], as well as with the antinociceptive effects of GYY4137 in the first stages of PTX-induced neuropathic pain [ 40 ] and in animals with CIPN induced by oxaliplatin [ 16 ].…”

Development of a Silicone-Based Polymer Matrix as a Suitable Transdermal Therapeutic System for Diallyl Disulfide

“…Recently, DADS was reported to relieve traumatic neuropathic pain in a sciatic nerve ligation model when given orally [ 16 ], as well as to attenuate Complete Freund’s Adjuvant-induced inflammatory pain when given intraperitoneally [ 17 ]. Similarly, the inhalation of H 2 S, as well as the intraperitoneal injection of the alkyl sulfide molecule dimethyl trisulfide (DMTS), have also been shown to diminish diabetic and traumatic neuropathic pain, respectively [ 38 , 39 ]. The involvement of TRPA1 activator sulfide compounds in nociception, as well as the extensive use of capsaicin—the potent agonist of another TRP channel, the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor—in form of transdermal patches for neuropathic pain [ 40 ], raised the question of whether TRPA1-stimulating agents, such as H 2 S and its donor compounds, could be applied in the form of a transdermal therapeutic system.…”